1. Field of the Invention
The present invention in general relates to a process for preparing an intermediate of an antihypercholestero-lemia agent, and in particular to a process for preparing compound 2 from compound 1, each as described below, by using tetraalkyl ammonium hydroxide as a hydrolytic reagent.
2. Description of the Related Art
Antihypercholesterolemia agents such as Simvastatin (compound 6), 6(R)-{2-8'(S)-2",2"-dimethylbutyryloxy-2'(S)-6'(R)-dimethyl-1',2',6',7',8' 8'a(R)-hexahydronapthyl-1'(S)-ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyr an-2-one are strong inhibitors of the biosynthesis of cholesterol. Simvastatin is prepared from the starting material lovastatin (compound 1). The 8'-ester group on the polyhydronaphthyl ring of the starting material, lovastatin 1, is first hydrolyzed to form 8'-hydroxy compound 2. The 4-hydroxyl group on the lactone ring of the 8'-hydroxy compound 2 is then protected with t-butyldimethylchlorosilane in an inert atmosphere at room temperature (about 20-30.degree. C.) in the presence of an acid acceptor such as imidazole to form a .beta.-hydroxy protected derivative 3. The 8'-hydroxy on the polyhydronaphthyl ring of the compound 3 is then acylated in one of two methods. The first method comprises treatment with the acid chloride of the desired acyl group in pyridine with 4,4-dimethylaminopyridine as catalyst. The second method comprises treatment of the 8'-polyhydronaphthol with the free acid of the desired acyl group and an N',N'-dicyclohexylcarbodimide with 4-pyrrolidinopyridine as a catalyst in dichloromethane. These procedures give the protected ester, compound 4. The removal of the silyl protecting group from the 4-hydroxy group of the lactone ring is then carried out, using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of the ester to give the desired compound 6, simvastatin. The reaction scheme of the above process is indicated below. ##STR1##
U.S. Pat. Nos. 4,293,496 and 4,444,784 disclose a process for preparing compound 2 from compound 1. The process includes heating lovastatin with an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, in a protoic solvent such as water or an alcohol followed by acidification and lactonization. Although the .alpha.-methylbutyryl ester of lovastatin is highly sterically hindered, employing strong base such as sodium hydroxide or potassium hydroxide for hydrolysis is disadvantageous because the base-sensitive .beta.-hydroxy lactone group tends to form eliminated side product extensively under this condition. Thus, in industrial applications, the weak nucleophilic base, lithium hydroxide, is used for the hydrolysis process. However, when lithium hydroxide is used, the hydrolysis process must be performed at an elevated temperature, for example 120.degree. C.-180.degree. C., for an extended period, (longer than 72 hours), and the yield after acidification and lactonization is not high, i.e. less than 80%. Moreover, lithium hydroxide can easily react with trace amounts of carbon dioxide in the reaction system and precipitate out as lithium carbonate. The precipitate will hinder the further work-up process.